Hepatocyte growth factor (HGF) receptor, also known as C-Met, is a tyrosine kinase receptor. Abnormal activation of C-Met is related to a poor prognosis of cancer, when there is a problem of C-Met overexpression. C-Met abnormality is also found in many types of tumors, such as hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), bladder cancer, liver cancer, kidney cancer, stomach cancer, breast cancer, squamous cell carcinoma, brain cancer, colon cancer, etc. C-Met abnormality can be expressed as increased expression, gene amplification, gene mutation or increased expression of HGF. In these abnormal circumstances, C-Met is activated in an abnormal state, which results in carcinogenesis and poor prognosis. Abnormal activation of C-Met will lead to tumor growth, formation of new blood vessels (angiogenesis, which can provide nutrients to the tumor), and help the cancer spread to other organs (metastasis). Inhibition of the C-Met signaling pathway is thus an important therapeutic strategy for the treatment of cancer.
C-Met inhibitors having pharmacological activity are described by Jiangsu Hansoh Company in the Chinese patent application CN201310173581.4 and the PCT application thereof (PCT/CN2014/072825). One of the compounds described is 9-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-yl)thio)-4-m ethyl-2H-[1,4]oxaazido[3,2-c]quinoline-3(4H)-one (referred to as “compound of formula I”).

The compound of formula I is a valid C-Met/HGFR (hepatocyte growth factor receptor) kinase inhibitor. As a C-Met tyrosine kinase inhibitor, the compound of formula I can effectively block the HGF/C-Met signal transduction pathway for the purpose of treating abnormal cell growth (e.g. cancer) in mammals. However, in the patent application CN201310173581.4 and the PCT application thereof (PCT/CN2014/72825), only an amorphous form of the compound of formula I was described. It is well known that the amorphous form of a drug means that the drug molecules aggregate in a disorderly manner, and the drug does not contain a significant lattice. The amorphous form of the drug has a higher thermodynamic energy state than the crystalline form, which results in thermodynamic instability. Thermodynamic instability leads to poor chemical stability, easy moisture absorption and solid phase transition. Accordingly, the quality of the drug is extremely unstable. Therefore, it is difficult for the amorphous form to be used in drug development. Furthermore, during drug preparation, the process of drug crystallization is an effective purification method. The resulting crystalline form also has the technological operation advantage of easy further purification, easy filtration, drying and so on. Therefore, it is necessary to further research and develop new crystal forms which have good crystallinity, moderate size, good solubility, and high stability in order to improve the bioavailability of the drug. The patent application CN201310173581.4 and the PCT application thereof (PCT/CN2014/072825) disclosed an amorphous free base of the compound of formula I. Said free base has a low solubility in various solvents, which is not conducive to drug dissolution in an animal or human body. Therefore, it is a very urgent task to research and develop suitable salt-form compounds in order to improve the dissolution rate and the solubility of the compound of formula I.
In summary, for the amorphous free base, further technical improvements are needed in drug purification, drying, storage, formulation, and dissolution and so on, in order to improve drug bioavailability.